Monthly Archives: June 2014

Last March, I wrote a column entitled Reality Check, featuring the work of Stephen Spindler. Spindler is a veteran researcher at UCRiverside, and perhaps the world’s foremost expert in the design and execution of longevity studies in mice. But Steve is a glass-half-empty kind of guy. And ever since I wrote that column, I’ve been thinking that I need to write about Spindler’s opposite number in Russia: Vladimir Anisimov is a veteran gerontologist at the Petrov Institute in St Petersburg, who has also been testing longevity potions on mice through a long career. Anisimov is a glass-half-full kind of guy. His best contribution to anti-aging medicine may be epithalamin, a treatment that has been hiding in plain sight for over thirty years.

An innovator with a deep knowledge of biochemistry, Anisimov has published theoretical as well as practical science. His lab has tested biochemical ideas about aging, as well as doing many studies on genetics and longevity in rodents and flies. He has reported and summarized results of other Russian labs in English-language journals.

Some of Anisimov’s findings are well-known to me, and therefore to followers of this blog and of my Aging Advice web site. Metformin reduces mortality and slashes cancer risk in people who take it as a medication for diabetes. Metformin increases life span of ordinary non-diabetic mice. Anisimov thinks it will do the same for non-diabetic humans, and I agree it’s a good bet. Melatonin, the hormone that regulates our daily cycle, is also found to prolong life span in mice. Melatonin in the blood is very sensitive to light exposure, and melatonin disappears with the dawn’s early light Anisimov found that sleeping in total darkness is better for longevity than exposure to light during the night. Here are two reviews by Anisimov of mostly Russian work on life extension with melatonin [2003, 2006].

(Unrelated to melatonin and to Anisimov: A recent study also suggests sleeping in the cold helps preserve insulin sensitivity.)

Another of Anisimov’s lines of research is less well-known to me, and I report here my first impressions. He has worked with “short peptides”, strings of less than 10 amino acids, that can act as signals or switches that control body chemistry globally. Short peptides are small enough to pass easily through the skin or through the blood-brain barrier. Unlike full-size proteins, short peptides tend to resist dismemberment by stomach enzymes. Carnosine and carnitine are familiar examples of di-peptides, consisting of 2 amino acids.

Here’s the theory: We know that gene expression is quite different in old and young people. In the literature, you find various interpretations and explanations why this might be true. But my interpretation is clear and simple: The body times its life cycle using gene expression. When we’re young, we express genes that make us grow. When we’re middle-aged, we express genes that keep us healthy. When we’re old, we express genes that destroy us.

“Gene expression” is the translation of DNA into proteins. Proteins are the signals and the workhorses of body chemistry. The translation is well understood since Francis Crick discovered the Genetic Code in the 1960s. But the language for determining which gene gets expressed when is apparently much more complicated, and it is just beginning to be decoded in the 21st Century. This is the science of epigenetics.

Among the signals that can locate a particular stretch of DNA, and turn it ON or OFF are short stretches of RNA called pi-RNAs, methyl transferases and histone de-acetylases. (I’m sorry to throw biochem jargon at you, but I’m excited to have just barely begun to educate myself about the fundamentals of epigenetics with a Coursera course this spring.) But the point is that these short peptides that Anisimov has been studying for 20 years work also as gene promoters and repressors – epigenetic signals that are more specific than the methyl transferases and less specific than pi-RNAs. Apparently they can affect whole categories of genes [ref].

Here’s a paper in which Anisimov summarizes 35 years’ experience with animal experiments, and some tantalizing human results as well. (One of the differences in Russian bio-medicine, for better and for worse, is that regulations about experiments on humans are more relaxed than in the US.) Here’s a table summarizing results in mice and rats. (As usual, life extension in flies is more dramatic, but less indicative of human benefits.) As you can see, this is a science that goes back to the 1970s, when the top two preparations were purified from epithalamus and thymus glands.

The thymus is a gland in the upper chest that trains the immune cells in our blood to attack invading cells, but to lay off our own body’s cells. As we get older, the thymus shrinks, and I believe this to be a basic cause of aging immune function, auto-immune disease, and increased susceptibility to infection. Thymalin was found to stimulate thymus re-growth and to rejuvenate immune function.

Epithalamin is also called epitalon or epithalon, and was discovered in extacts from a region of the brain called the epithalamus. This region contains the pineal gland, or “third eye”, which controls wake/sleep cycles and is the body’s source of melatonin. Like thymalin, epithalamin is a string of four amino acids. Thymalin generated excitement in the 1980s, until epithalamin stole its thunder. Not only did it extend life more consistently, but its effect on thymic growth was found to be superior to thymalin.

In the table, epithalamin has been the best-studied short peptide, and it has the best record for life extension in rodents. In a separate table, the same paper shows that epithalamin and thymalin suppress cancer in rodents. There is also evidence of large reductions in mortality when epithalamin was given to older human subjects:

In addition, it has recenty been reported (2003, 2004) that epithalamin is a telomerase activator. Skeptics (Spindler in particular) point out that caloric restriction is such a strong influence on life span that many treatments will appear to show benefit only because they affect appetite. Some of the studies do measure food intake, and find that epithalamin is able to increase lifespan without decreasing food consumption.

(Epitalon is available commercially, but not from most supplement sources. Recommended dosage is usually less than 10mg, but experience with different dosages is very limited.)

Reference: a crash course in mid-brain anatomy

Here’s a picture of the human brain, courtesy of Wikipedia. The mid-brain is the endocrine function, where computations made with neurons are translated into prescriptions for internal secretion.

The epithalamus is shown in cherry. It includes the pineal gland, the so-called “third eye” which is responsible for the body’s light-sensitive clock, and where melatonin comes from. The hypothalamus is shown in lime. It includes various “nuclei”, notably the suprachiasmatic nucleus, which is the closest thing science has found to a developmental clock. The pituitary is also part of the hypothalamus, and secretes hormones involved in the life cycle and the menstrual cycle: HGH, LH, FSH, TSH and sex hormones.

Conclusions

All of this looks so promising that I wonder why there hasn’t been more follow-up, and why American researchers haven’t built on the Russian results. Russian science tends to be more adventurous than American science. That doesn’t mean they make more mistakes. The problem with American science is that it is too rigidly institutionalized and controlled within an establishment. It is usually not possible to get funding to ask a question to which you do not already know the answer. So the mistakes of American science are more likely to be under the header “confirmation bias”, while Russian science is more likely to be offering results that may not pan out. This seems to be a well-established field, with positive results that have been affirmed over decades in different labs with flies, rodents, and humans. My web search identified no dangers or reports of toxicity. I’d say it’s high time the American and European gerontology communities picked up this thread. In the mean time, please comment if you have any experience with epitalon or other short peptides.

It has been a major triumph of human civilization: Never before in evolutionary history has a species lifted itself from Darwin’s Struggle for Existence, and created a safe, secure environment in which a majority of individuals may expect to live out a full life expectancy and die of old age. You and I take for granted that aging is the greatest hurdle that we face in our quest to live a long, long time. Let’s hope this is true.

Let’s do more than hope. Let’s remember that aging evolved in order to keep ecosystems in balance, to keep populations from outgrowing their resources. If we are at the forefront of the movement to extend individual life span, we must also be at the forefront of a movement to lower birth rates and shrink the human footprint.

Me, my and mine: The Human Species and the Terrible Twos

Before we learned empathy, before we learned to share and to wait our turn, before we learned to provide for others and to trust that our needs would be provided in turn—we were Terrible Two-year-olds. Everything was me, my and mine.

Before humanity, Gaia was a diverse and wondrous beast, a many-headed Hydra, with different local faces in mountain and forest and desert and ocean environments, every acre a unique ecosystem.

Henry David Thoreau spoke of teaching the earth to say “beans” instead of “grass” — “this was my daily work.” The history of humanity on this planet has been to divert the Earth’s primary productivity from the diverse cycles and epicycles in the tangled bank that is nature, to align the primary productivity in the service of man, to feed and clothe and house us, to provide our comfort and transportation and amusement.

As humans spread out of Africa some 60,000 or was it 200,000) years ago, every place that we appeared, the charismatic megafauna would disappear, and humans would replace them at the top of the food chain. Giant bears in Europe, Giant Sloths in South America, Mastodons and Sabre Tooth Tigers in North America, Great Awks in Iceland, 7-foot Kangaroos and 3-ton Wombats in Australia, 8-foot Moas in New Zealand (the original Big Bird). All the largest animals that thought they were safe from predation succumbed to the chiseled flint spearheads and the clever tricks and traps of small bands of humans. Ecosystems were made over in our service.

For thousands of years, we humans thought only of me, my and mine. We understood that as we domesticated the planet there would be victims. There are winners and losers in the game of life. It is our mission, our destiny to make sure we are among the former.

Recent centuries have seen an acceleration of this process, impressive increases in the conversion of grass to beans. Hunting and gathering yielded to agriculture, then factory farms. Monoculture has replaced the tangled bank. Greater triumphs for humanity, greater losses for the lower plants and animals that we displace.

Blowback

We all live in artificial environments, “Little we see in nature that is ours,” wrote Wordsworth over 200 years ago, and I daresay he never saw Walmarts or even Manhattan. We take a moment to remember the plight of the dying birds and the frogs, the poor frogs – the world’s amphibian populations have been disappearing at the rate of more than 3% per year. We miss nature, we truly do, but we imagine all the same that their loss is our gain. Man is no longer dependent on the ecosystem that birthed us. We can live in an engineered world. We will cover the Earth with farms and factories and housing, and human life will go on, even if what we know as Nature is dead as a Dodo.

What if it isn’t true? What if human life is more dependent on a functioning ecosystem than is apparent? We are already coping with a precipitous decline in pollinating insects by renting out mobile beehives to our farmlands. We don’t really know to what extent our farms are dependent on the ambient ecology. Bacterial communities recycle carcasses into nutrients. Wetland ecologies purify water. Oceans buffer our atmosphere.

Could you kindly rephrase that in equivocal, inaccurate, vague, self-serving and roundabout terms we can all understand?

California grows half of the produce consumed in the United States, and continues to do so by mining a fossil water table which is down 40 feet in the last 40 years. The American Midwest is the breadbasket not just for the US of A, but for much of the world; and there a rich layer of topsoil, laid down over tens of thousands of years, is being washed into the Mississippi in a few decades.

Putting a dollar value on “ecosystem services” may be an absurdity, but here is a study that sought to catalog some of the value of Nature, and stopped when they got to a number that was twice the economic output of the entire world.

We don’t know how much we can grow or how many people we can support on this planet sustainably, because we’ve never tried. But there has been one small-scale experiment that may be instructive. In the late 1980s, visionary scientists constructed Biosophere II [link] in the Arizona desert. It was conceived as a self-contained microcosm of Planet Earth (re-named “Biosophere I”), complete with farmlands, forest, wetlands, a desert, a miniature ocean with coral reef and a tropical jungle modeled on the Amazon – all in an enclosed dome that covered p acres. The biological community was engineered to be a closed, self-sufficient artificial ecosystem, recycling oxygen with its plants and purifying water in its wetlands. There was solar energy aplenty.

The experiment was a disaster. Atmospheric oxygen was permitted to decline to 2/3 of its ambient value before the project doctor (well-known and well-loved by many of us in the life extension community) rebelled and insisted on fulfilling his Hippocratic oath. Neither was the community ever self-sustaining in food or clean water. The residents/scientists/pioneers had no idea what they had committed to, and relations became contentious when the basics of life were in short supply. Stories survive of smuggled food, fistfights, and residents who took survival into their own hands, breaking windows to permit air exchange.

Resource Wars

If it becomes clear that the planet cannot support all of us as resources begin to be in short supply, we may imagine some of the diverse responses of people and governments. For many people, hardship brings out our noblest altruistic nature. For others, there will be food fights and resource wars. Me, my and mine. Governments have already offered us hints about the lengths to which they are willing to go to “preserve order” in a crisis.

Healthy, caring and progressive human minds do better not to think about such things, as their contemplation can make us feel helpless and drag us into depression. Joanna Macy has devoted her career to helping us keep our sanity as we advocate for peace and environmental sanity.

Latency

Chemists call it “latency”. Physicists say “hysteresis”. Ecologists speak of “delayed functional response”. The meaning is that systems have an inertia that keeps them looking the same for awhile, even after everything, everything has changed. You can slowly raise the temperature of a glass of water until it’s 10o above boiling, and it looks like a calm liquid, not a bubble in sight. But then touch it or disturb it or drop in a grain of sand and the water explodes. (People have been scalded taking a superheated cup of coffee out of the microwave.)

And so may it be with species extinctions. The producer species have not been keeping pace with consumption for quite some time, but the consumer species goes on, apparently thriving, continuing to increase in number, though they may notice it is a little more difficult than usual to forage the evening meal. By the time the predators realize that something is awry, the game is played out and long past over. There’s no road home.

The reason can be explained in terms of exponential mathematics: a depleted prey population grows very slowly, even as the predator population is at maximum demand. Or intuition tells us the same thing: when food becomes scarce, the predators step up their hunt effort and do their best to maintain their quality of life (and their fertility) until food becomes so scarce that it is too late. The prey species, if not extinct, is at such a low level that it will take a long time to recover, long enough for most of the predators to starve. The earth’s ocean ecologies have already been transformed beyond recognition by industrial-scale fishing methods.

In 1944, the US Coast Guard introduced 29 reindeer on the island of St Matthew off Alaska. There had been no large mammals on the island before, and no natural predators. It was an experiment to see if a hunting preserve could be established. The reindeer population grew steadily at about 30% per year, first surpassing the number the island could support sustainably in about 1958. That was about 2,000 animals. But by 1963, inertia carried the population over 6,000. The next winter was rather harsh, not extraordinary, but enough to devastate the over-extended population. When wildlife wardens landed on the island the following spring, 42 reindeer remained alive [ref].

The Sixth Extinction

Between the advent of multicellular life and the current era, there have been five major extinction events, in which between 30% and 80% of all extant species vanished on a timescale shorter than can be resolved in archaeological records. These were spread over 500 million years. We are now in the midst of the Sixth Extinction, sometimes called the Anthropocene Extinction, and it is estimated that there is already sufficient inertia in the process to insure that a substantial fraction all extant species will perish in ensuing decades, no matter what conservation efforts are undertaken, and no matter what future direction is taken by human civilization.

In 2002, world leaders represented at the Convention on Biological Diversity committed to a program targeting a significant decline in the rate of species extinction by 2010. It was assumed at the time that conservation measures at the fringe of the mainstream economy would be adequate to achieve this end. But by 2010, it was clear that this program had failed dramatically, and that the loss of biodiversity is essentially linked to the core character of human economy.

I have explained in previous blog posts my belief that ecosystems are highly co-evolved for stability. Large-scale. complex ecosystems have the property of being highly interdependent, and redundant, which creates a resistance to small disruptions. The same structure also creates a vulnerability to large disruptions. There is a “domino effect”: Once a threshold of loss is exceeded, the entire system becomes vulnerable to collapse. It is theorized that most of the species lost in the previous five extinctions succumbed to this sort of “collateral damage”.

Democracy

David Wilson has proposed that democracy is an evolutionary development of seminal import, and is what distinguishes human organization from other successful social species. Humans communicate and negotiate, and are able to arrange their cooperation in the interest of a diverse community. Contrast this to eusocial insects, for example, which enlist an army of workers in the interest of a single genome. The human analog of these systems is oligarchy and aristocracy, which Wilson sees as pulling us back toward a lower and less powerful stage of evolutionary development.

We live in a time when most of the developed world pays lip service to democracy, but in reality, deep distortions to democracy pull public policy into the service of short-term corporate profits, and a very small, very wealthy minority.

Democracy alone may not be sufficient to take us from imperial wars and an extractive relationsihp to nature all the way to world peace and environmental stewardship…but it’s a big step in the right direction. Corporatocracy is carrying us in the wrong direction,180 degrees at a rousing gallop. The people have consistently expressed more sensitivity to nature than the politicians, and there has never been a war but that the politicians have had to drag the people into it with ominous appeals to fear more than patriotism.

There’s nothing I can do, so why are you reminding me of this shit?

I return to Wordsworth. I love this poem (and am grateful to my late father-in-law for introducing me). It was written in 1806.

THE world is too much with us; late and soon,
Getting and spending, we lay waste our powers:
Little we see in Nature that is ours;
We have given our hearts away, a sordid boon!
The Sea that bares her bosom to the moon;
The winds that will be howling at all hours,
And are up-gathered now like sleeping flowers;
For this, for everything, we are out of tune;
It moves us not.–Great God! I’d rather be
A Pagan suckled in a creed outworn;
So might I, standing on this pleasant lea,
Have glimpses that would make me less forlorn;
Have sight of Proteus rising from the sea;
Or hear old Triton blow his wreathed horn.

Most of us live busy, over-scheduled lives, committed to family, friends, and more projects than we are able to complete. We feel that much depends on our efforts, and, in the last analysis, we are all alone.

We live, after all, in a hyper-individualistic culture, with a sense of who we are that is probably anomalous both across history and across nations. Many Asian cultures are subtly more collective and cooperative than ours. Hunter-gatherer cultures of our hominid ancestors (and extant hunter-gatherers today) are strikingly more communal in their organization. Much of the angst and yearning that we feel from day to day (feelings we have learned to ignore, or to blame on our own failings) may be an echo of our longing for re-connection to nature and to each other. We were never meant to go it alone.

Our individual mortality looms large, perhaps especially so for members of the life extension community. Of course, fear of death has a biological basis and evolutionary roots. Mourning and long sadness over the loss of a loved one is ancient – gorillas and even elephants mourn their dead. But this sense that my individual consciousness is all that there is, that it depends on this body, that all is over when the light goes out, an absolute finality – this is an abysmal terror that most people historically have not lived with, and even most cultures today do not feel.

Entertain the possibility that our sense of self may be deeply distorted by culture, that there is another way to feel about our very existence. Explore opportunities for collective political action, not only as a way to save our planet, but also to reconnect to each other, to nature, and to our own souls.

Last week, an article about the cell biology of fasting made headlines in the science news press. Valter Longo cites evidence that a 3-day fast can rejuvenate our immune systems, with broad anti-aging benefits. 4 or 5 days may be better yet.

Socially, I was a late bloomer, clinging too tightly to love, driving away partners until I was in my 20’s. I took a full year to allow Marsha into my heart. Four years later, she broke up with me, and it launched a full-scale spiritual crisis, beginning with three days in which I had no interest in eating.

Those of you who have probed my Aging Advice page know that I fast a day a week, water only from Wednesday evening to Friday morning. I have grown quite comfortable with this routine. I ease off other disciplines on Thursdays, take a day off from aerobic exercise, allow myself to sleep more and be less productive. I still do yoga, and like to take long walks on Thursdays.

But not since I was 28 have I fasted three days. Monday morning, I awoke with the thought that this is as good a time as any to begin a three-day fast. If I wait longer, I will have time for fear and worry. My mind will play tricks on me, making it harder than it has to be.

I first became acquainted with Valter Longo’s work when, in 2004, he published a remarkable paper in Journal of Cell Biology based on work he did on yeast cells for his dissertation almost a decade earlier. The results were considered so unlikely that it had taken him that long to convince a journal editor to take a chance and publish them. What Longo had discovered was that when he starved a colony of yeast cells, about 95% of the cells would commit suicide, using the controlled death mechanism of apoptosis. They would disassemble their proteins, dissolve the cell membranes, and turn themselves into food for the remaining 5%.

Impossible! replied the reviewers, schooled in traditional evolutionary theory. How could such an adaptation evolve? The colony must be closely related genetically, and how could the 5% be genetically different from the other 95%? And whatever that difference was, the 5% would pass on their genes, the genes of the 95% would perish, and the next generation would no longer have the suicide adaptation. We know this from basic theory, said the reviewers. Longo must have made a mistake in his biochemistry. These cells are not committing suicide – they are starving to death.

“Extraordinary claims require extraordinary evidence.*” The paper was returned to him over and over, demanding more and more validation that what he saw was really apoptosis. It took ten years before the paper was finally accepted for publication.

Today the fact that Longo discovered is widely accepted, though the message for evolutionary theory has yet to filter through. But Valter saw the full implication of his work: If yeast cells had failed to read the basic textbooks in population genetics, what other animals and plants might have been similarly negligent? Yeast cells are just one example of programmed death in the biosphere. I was honored and excited the following year when Valter invited me to join him and Vladimir Skulachev in a paper for Nature Genetics on Programmed and Altruistic Aging.

In the intervening decade, Valter has been a ubiquitous presence in the biology of aging and of caloric restriction. Of many creative innovations he has introduced, the one he is best know for is fasting as a cancer treatment. He has documented that a three-day fast before chemotherapy has a powerful and extraordinary effect on the metabolism: The body’s normal cells are in a heightened state of protection, and are much more resistant to chemical toxins. Hence the discomfort, headaches and nausea that generally accompany chemotherapy are attenuated – not to mention the long-term damage. At the same time, the cancer cells are sensitizedby the fast, so that more of them are knocked out by the chemo treatment. This is a win-win for the patient, but Valter has undertaken a long and arduous campaign to convince oncologists that such a simple protocol could be so effective. Worst of all, no one can make a dollar from fasting.

And what of the rest of us, who don’t have cancer? This is the subject of Valter’s most recent work, that made science news headlines last week. He puts together evidence from mice and humans that the three-day fast is a boon for us as well. (Here is the full text, and here is an editorial in the same issue of Cell Stem Cell putting the article in context.)

Evidence in this week’s Longo Article

The experiment around which the paper is written involves depriving mice of food, then looking at the stem cell environment in their bone marrow. Fasting actually increases the number of active stem cells in the bone marrow, even as the circulating white blood count is down sharply. Two chemical signals are identified that mediate the process: Both IGF-1 and PKA are down-regulated with fasting.

IGF-1 (insulin-like growth factor) is an old friend, first discovered in worms in the 1990s, and later identified as a pro-aging hormone generally. PKA (protein kinase A) is less well known, and has many independent functions, de-activating several different signals by tacking on a phosphate group. The cell’s energy cycle uses ATP, which yields energy and is recycled in its low-energy form, AMP. Accumulation of AMP occurs when energy stores are low, and this signals a reduction in PKA.

The article makes a point that, though the benefits of long-term caloric restriction have been studied extensively, this kind of rejuvenation of the immune system has never been observed with CR alone.

Much of the article is theoretical, connecting decline of the immune system to many of the medical issues associated with aging. Arthritis and even Alzheimer’s disease are rooted in auto-immune reactions. The steep rise in cancer with age is believed to be related to the immune system’s failure to detect cancer in its early stages and to eliminate pre-cancerous cells. It is to be hoped that rejuvenating the immune system might have broad anti-aging effects.

Why does it work? Evidence for programmed aging

In write-ups of this material, the failure of stem cells with age is described as “dysregulation”, and the reason the strategy works is attributed to a clearing out of damaged and ineffective immune cells from the blood, as they are converted by the body to food. Perhaps you have noticed that this makes little sense. Certainly Valter knows this better than anyone, given his history, but he has chosen not to fight the abstract battle about evolutionary theory, because he knows it would likely interfere with the credibility of his other, practical and life-saving work.

The point is that if the fasting body is able to rejuvenate and multiply the bone marrow cells that are responsible for blood and immunity (hematopoietic stem cells), then it is obvious that the body could do this as well or better when it has plenty to eat. If it wanted to. The fact that hardship and deprivation can induce the body to rejuvenate implies that aging is a programmed choice. Even when it looks as though the cells are suffering damage over time, that damage is entirely avoidable (indeed, repairable), and it is only with chemical switches that the repair mechanisms are turned off as we age. In PKA and IGF-1, Longo has identified two of the signals that keep the repair mechanisms dialed down, and make our health deteriorate with age.

Why is the body intent on killing itself? It is an adaptation for population regulation, a response to natural cycles of boom and bust in population size. When times are good, the population expands too fast. Aging is a way of slowing down the population boom. This is why we age more rapidly when there’s plenty to eat. In times of famine, there is already plenty of death, and the danger is the opposite – that the population might plunge to extinction. This is why aging backs off in the face of hunger. (Ideas in this paragraph are not yet standard evolutionary theory, but this is a theme that I have developed in computer simulation, and it is the core of my contribution to publications in the field.)

Fasting in Ancient Religious Traditions

Though they are not controlled and not founded in a knowledge of biological mechanisms, traditional writings nevertheless embody experience of large numbers of people over a long period of time, and I look to them for ideas, for cautions and confirmations. Before writing this piece, I had the impression that fasting was recommended in many religious traditions, and I eagerly googled associations with the 3000-year-old Ayurvedic (longevity) tradition of India. I was surprised to learn that fasting for more than a day is regarded as an extreme practice, and that Ayurvedic texts don’t provide prescriptions or recommendations for long-term fasts, but rather cautions against fasting, suggesting that fasting practice has been prevalent for a long, long time, and the ancient Ayurveda was already reacting against it.

Frequent 12-24 hour fasts, however are recommended, even prescribed in the Ayurveda. Eating the main meal early in the day is a practice that ancient traditions and modern medicine agree on. Avoiding food for several hours before bedtime is part of yogic practice. For Buddhist monks in the Theravada tradition, all eating is confined to the morning hours, implying a daily fast of 16 hours.

Implications for the clinician, for you and me

I find it remarkable, if no longer quite surprising, that in write-ups of the therapeutic effects of fasting, medical professionals and researchers focus on what we can learn that will help us produce a drug that mimics the benefits of fasting. Fasting is providing all the benefits with little or no downside (except temporary hunger, need for warmer clothing); but medical science is busy search for drugs that will probably target just some of the signals that fasting sends, and will probably have more serious side-effects than fasting. Longo says that the constellation of benefits from fasting “would be difficult to achieve with any pharmacological or other dietary intervention.”

It is deep in the culture of today’s medicine that the patient is passive and it is the doctor who is the agent of healing. Medical professionals de-emphasize all that the patient can do with diet, exercise and life-style modifications to improve his own health, despite the proven power of these regimes. Part of the problem is in the conection to capitalism, which creates a focus on what can be healed profitably, ignoring remedies that cannot be sold.

Fasting and weight loss

It is my experience that I don’t lose weight from fasting, presumably because I eat more before and after a fast. Other people I know have reported similar experiences, and both ancient texts and modern medical advice agree that fasting is not an effective way to lose weight for most people. That doesn’t mean it won’t work for you, if you have experience to the contrary.

I’m now in Day 3, and it seems long only psychologically. In my weekly Thursday fasts, I sometimes experience headaches (one week in 5 or 6), and that hasn’t happened. I have the luxury of no busy schedule, no deadlines. That’s a good thing, because productivity on fast days is not reliable. During fasts, I don’t have the focus to be able to write computer code, and writing is often slow. But often deep and creative thoughts are given to me during fasts.

I can sit contentedly for long periods of time without feeling a need to accomplish anything, or even to get up. I tend to a shorter night’s sleep, but enjoy naps during the day. Once in my life I tried public speaking on a day I was fasting, and I won’t do that again. Words come out more slowly, trying the patience of the audience. (My one experience was speaking to the Caloric Restriction Society, and my audience understood and were patient.)

How long is optimal?

I wrote to Valter yesterday, asking this question. Does he have evidence from people suggesting how long it takes for the immune reset? Is it different for people who start with a lot of fat on their bodies compared to people who have nothing in reserve? His answer was short and to the point:

“3 days is optimal for mice. For humans 4-5 minimum, depending on what you are trying to achieve”

You can already tell I have a lot of faith in Valter as a scientist, and it is easy for me to believe that, from his experience, he knows more than he is able to publish. So I’m deep into Day 4 as I finish writing this. I’m a little spacey and my rhythms are disrupted, but I’m not suffering or food-obsessed. I plan to start fruit or juice soon.

Mea culpa. Almost three weeks ago I promised to do a little reading and report back on what to believe about cholesterol and heart disease. It was hubris to imagine that I would be able to untangle the thicket of conflicting claims with a short course of study. Today, my goals are far more modest, and I offer my scaled-back conclusions. Here, I offer a tentative analysis, which I hope will prompt people more knowledgable than I to refine and correct the message.

The mystery

The standard medical paradigm says that eating saturated fats contributes to higher LDL cholesterol in the blood, and that higher LDL is associated with greater risk of CVD (cardiovascular disease = heart attack and stroke). The mystery which I identified last month is that there is strong evidence both for and against this hypothesis in the mainstream medical literature.

Why the disparity?

Certainly one reason there is so much difficulty obtaining agreement in the field is that the majority of scientists doing research on cholesterol are funded by drug companies that have billions riding on the results. This is not a question of “honest” science vs “corrupt” science. It is simply unreasonable to expect that a scientist working for a statin manufacturer feels free to pursue his study objectively, and to follow the data wherever it leads. It is hard to know the extent to which drug money has corrupted the science of cholesterol, but we can be assured that it is substantial.

Despite this major bias, I don’t think that the relationship between cholesterol and heart disease is entirely a mistake or a fraud. Even the harshest critics of the cholesterol establishment (Fred Kummerow, Stephanie Seneff, John Abramson, Sally Fallon) admit that there is some correlation between saturated fat in the diet and cholesterol in the bloodstream. Similarly, there is good evidence that risk of heart disease is correlated with LDL cholesterol. A new test based on the size of the LDL particles is much more predictive – see below.)

Correlation and Causation

If A is correlated with B and B is correlated with C, it does not follow that A must be correlated with C. Furthermore, even if A is correlated with C, it may be that A does not cause B, or B does not cause C, so that changing A may have no effect (or the wrong effect) on C.

To be concrete: It may be true that saturated fat in the diet is correlated with high LDL, and high LDL is correlated with high CV mortality, and still cutting saturated fat does not affect CV mortality.

Most studies linking saturated fats with LDL cholesterol have been positive [ref], and most studies linking LDL cholesterol with risk of CVD have been positive [ref]. But studies attempting to link saturated fats in the diet with a higher risk of CVD have mostly been negative [ref]. This suggests that we don’t understand the underlying mechanism behind heart disease very well, and that much of what we have done in the name of prevention may have been misdirected at intermediate targets that were not causally related to heart disease.

What is true of saturated fat reduction is even more true of statin drugs. It is certain that statin drugs improve the cholesterol profile. It is less clear that statin drugs save lives, and it is certainly not true that statin drugs are the best prevention strategy.

It is very convenient to have an intermediate measure (like LDL cholesterol) so that you can tell whether an intervention is working without having to wait for large numbers of people to die. If we look for the effect of some new treatment on LDL, we can test a small number of patients and know within a few months whether it is working; but if we are looking all the way to the bottom line (how many people taking this new treatment are dying of heart disease?) then the study must involve large numbers of subjects, followed over many years.

Almost all of what we thought we knew about saturated fats, cholesterol and CVD has been based on indirect inference. We may have to start over, using the more costly and rigorous approach based on counting CV events in large numbers of people.

Blood Tests

In the 1960s, people were tested for total cholesterol in the blood, which was certainly the wrong indicator. So bad, in fact, that total cholesterol is inversely correlatedwith all-cause mortality risk. In recent decades, the standard test has been the ratio of LDL to HDL cholesterol. These are not two different kinds of cholesterol, but rather variations in the chemistry of the droplets that transport cholesterol in the bloodstream. Cholesterol is not water-soluble, so it is carried through the blood to all the places it is needed packaged in little droplets, These droplets come in low-density and high-density, large and small. “LDL” is “bad cholesterol” and it refers to the low-density droplets. “HDL” is “good cholesterol” and it refers to the high-density droplets.

Just in the last few years, there is a new blood test, which is a much better indicator of risk of heart disease and stroke than were LDL and HDL. It is a subset of the LDL droplets, the small ones, that are the basis of the new test. [Early article, 1997. large Scandinavian study, 2014.]

(I don’t want to say the small droplets are the culprit, or the cause of heart disease. It is still unclear whether relationship between the blood test and heart disease is a causal one. In other words, if we target therapies to reduce the scoe on the small particle test.)

You may want to make sure that small particle LDL is reported the next time you get a health check-up and blood test. It is sometimes reported as LDL III, or LDL-B. But the larger significance of this new, more accurate test is that it should make future research studies quicker and more efficient. Assuming that causality can be established, we will have, for the first time, a way of knowing whether a preventive therapy is working without having to wait ten years and see how many people have heart attacks.

Stay tuned…

Statins

The scale on this chart is 100 million prescriptions in the US alone.

It is probably true that statin drugs have saved millions of lives, if the alternative is defined as inaction in the face of heart risk. It is also true that statins are the most over-prescribed medications in the Western world, that their benefits are modest and come at a cost in side-effects that can be devastating in the long run. There are better ways to reduce cardiovascular risk, many of which have no side-effects, or side-effects that are wholly beneficial.

The way statins work is by impeding the synthesis of cholesterol. This is the wrong target. We need cholesterol. As I explained in my last post, cholesterol is what makes cell membranes in animals pliable. Cholesterol is also an intermediate product that the body uses to make essential hormones. Cholesterol is necessary for neurons in the brain. If we artificially suppress the body’s production of cholesterol, we are asking for trouble.

Statins also have a powerful anti-inflammatory effect, which may be the entire reason for their effectivenesss in lowering mortaliy. There are safer antiinflammatory agents available, including fish oil and aspirin, which seem to be the easiest route to lower cardiovascular risk.

Statin side-effects include:

Increased blood sugar, leading to diabetes

Reduced CoQ10, leading to muscle weakness and oxidative damage

Reduced levels of other hormones, including sex hormones that are synthesized from cholesterol

Muscle pains

Weakness

Low energy

Cognitive impairment

Arthritis?

Parkinson’s Disease?

The first item is the most troubling. Statin drugs increase blood sugar, and increased blood sugar signals the body to age more rapidly. In the long run, this has got to be bad for heart disease risk, and also for all other causes of mortality. Trading heart disease for diabetes is not a good bargain. Blood sugar (particularly fructose) also combines with cholesterol to create the chemical species that is most damaging. Stephanie Seneff explains:

Worse than that, once LDL particles have finally delivered their contents, they become “small dense LDL particles,” remnants that would ordinarily be returned to the liver to be broken down and recycled. But the attached sugars interfere with this process as well, so the task of breaking them down is assumed instead by macrophages in the artery wall and elsewhere in the body, through a unique scavenger operation. The macrophages are especially skilled to extract cholesterol from damaged LDL particles and insert it into HDL particles. Small dense LDL particles become trapped in the artery wall so that the macrophages can salvage and recycle their contents, and this is the basic source of atherosclerosis. HDL particles are the so-called “good cholesterol,” and the amount of cholesterol in HDL particles is the lipid metric with the strongest correlation with heart disease, where less cholesterol is associated with increased risk. So the macrophages in the plaque are actually performing a very useful role in increasing the amount of HDL cholesterol and reducing the amount of small dense LDL.

Perhaps the clearest message to come out of my reading is that there are better methods of lowering CV risk than statin drugs, and that people taking statin drugs should be looking for ways to replace them with measures that have beneficial side-effects. I divide these into two categories:

(1) those whose mechanism is like statins, and may lead to some of the same problems

Red yeast rice is a natural product with much the same effect profile as statin drugs, but with milder side-effects. It may provide an alternative for people who experience muscle pain from statins , though it still interferes with CoQ10 and hormone production.

Resveratrol acts at a higher level, promoting the SIR-T genes that have many downstream effects: increasing pliability of hardened arteries, reducing blood clots that lead to heart attack, and also lowering LDL cholesterol

Tree mushrooms used in Chinese soup (Auricularia) are quite effective in lowering LDL, and I have not found information about the mechanism. [ref, ref, ref]

Fish oil (either from fish in the diet or from capsules) seems to reduce heart risk more consistently and more effectively than anything else, with side-effects that are almost all positive. It works on HDL:LDL ratio by a mechanism that is not well-understood, and it is also anti-inflammatory, which lowers risk of cancer and Alzheimer’s as fringe benefits.

Congenital high cholesterol

There are a number of genetic defects that can cause high LDL cholesterol. Some can be tested, but most cannot. The defects are relatively rare (1/500) but have a substantial effect on life expectancy [ref].

There is a particular mutation on chromosome 19 that is responsible for high levels of LDL cholesterol, and experts on both sides of the divide agree that it is associated with a significant decrease in life expectancy and should be treated. Traditional treatment is based on extra-high doses of statins. Alternative treatments are available that are less well-documented but show indications they may be more effective than statin treatment, with fewer long-term side-effects. I recommend this article from Life Extension Magazine.

Separating saturated fats from other factors in a meat-based diet

Vegetarians enjoy lower mortality rates. How much of this is due to lower saturated fats, how much to high fiber, how much to micronutrients from fruits and vegetables? And how much is an artifact from the association between vegetarianism and better self-care in other areas? In this same study , vegetarians who ate fish had 10% lower mortality (over 6 years) than vegetarians who ate cheese and eggs. Perhaps this is an indication that saturated fats are bad for you, and fish oil lowers inflammation as well as blood cholesterol. This study suggests that the difference may be more about benefits of fish than of hazzards of eating eggs and dairy.

A diet high in vegetables is our first-line defense.

(This is the last paradox, I promise!) I began by noting that the correlation between saturated fat in the diet and cardiovascular risk is weak or non-existant [ref]. But we know that saturated fat intake is highly-correlated with animal foods in the diet, and animal products lead to higher overall mortality. This suggests that it is something else about the plant-based diet, besides low sat-fat, that is giving the benefit.

Coming back to my daughter’s question

My daughter is 28 years old and a vegetarian. Last month she asked me, “I have high blood cholesterol. Should I be avoiding coconut oil and cocoa fat?”

From three weeks of research, my answer has to be

(E) It cannot be determined from the above information.

Cardiovascular risk in the context of other sound advice

Lots of exercise, weight control, low-carb diet, fish oil, daily aspirin all contribute to lowering risk of heart disase, and in the aggregate are far more powerful than statin drugs, with other health benefits as a free fringe benefit.